A Novel Method to Induce Cartilage Regeneration with Cubic Microcartilage.

Cartilage tissue is characterized by its poor regenerative properties, and the clinical performance of cartilage grafts to replace cartilage defects has been unsatisfactory. Recently, cartilage regeneration with mature chondrocytes and stem cells has been developed and applied in clinical settings. However, there are challenges with the use of mature chondrocytes and stem cells for tissue regeneration, including the high costs associated with the standard stem cell isolation methods and the decreased cell viability due to cell manipulation. Previous studies demonstrated that cartilage can be regenerated from chondrocyte clusters that contain stem cells. Based upon some of the existing techniques, the goal of this study was to develop a novel and practical method to induce cartilage regeneration. A microslicer device was developed to process cartilage tissues into micron-size cartilage (microcartilage) in a minimally invasive manner. We evaluated microcartilage sizes and demonstrated 100-400 µm as optimal for generating a high cell yield with collagenase digestion. In addition, autologous intrafascial implantation of the composites of microcartilage and an absorbable scaffold with a slow-release system of basic fibroblast growth factor (bFGF) was carried out to induce cartilage regeneration. Our results demonstrated that the extent of bFGF diffusion depends on the size of microcartilage, and that cartilage regeneration was induced most effectively with 100 µm of microcartilage via SOX5 upregulation. These findings suggest that cartilage regeneration is possible with microcartilage as a source of cells without ex vivo cell expansion.

Wound healing delays in α-Klotho-deficient mice that have skin appearance similar to that in aged humans - Study of delayed wound healing mechanism.

Skin atrophy and delayed wound healing are observed in aged humans; however, the molecular mechanism are still elusive. The aim of this study was to analyze the molecular mechanisms of delayed wound healing by aging using α-Klotho-deficient (kl/kl) mice, which have phenotypes similar to those of aged humans. The kl/kl mice showed delayed wound healing and impaired granulation formation compared with those in wild-type (WT) mice. The skin graft experiments revealed that delayed wound healing depends on humoral factors, but not on kl/kl skin tissue. The mRNA expression levels of cytokines related to acute inflammation including IL-1ß, IL-6 and TNF-α were higher in wound lesions of kl/kl mice compared with the levels in WT mice by RT-PCR analysis. LPS-induced TNF-α production model using spleen cells revealed that TNF-α production was significantly increased in the presence of FGF23. Thus, higher levels of FGF23 in kl/kl mouse may have a role to increase TNF-α production in would lesion independently of α-Klotho protein, and impair granulation formation and delay wound healing.

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity.

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1(high)) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1(high) cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1(high) cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1(high) cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1(high) cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1(high) cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1(high) cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.

Corded and Hyalinized Endometrioid Endometrial Carcinoma: A Rare Case Treated With Robot-Assisted Surgery.

Endometrial carcinoma is the sixth most common cancer among women worldwide. Minimally invasive surgery (MIS) has become the preferred treatment, offering similar survival outcomes to laparotomy with lower complication rates. Corded and hyalinized endometrioid carcinoma (CHEC) is a rare and diagnostically challenging variant of endometrioid carcinoma, first described in 2005, characterized by a biphasic appearance of traditional low-grade endometrioid adenocarcinoma and corded and spindled cells embedded in a hyaline stroma. A 55-year-old nulligravid woman presented with abnormal genital bleeding for 10 days. Initial evaluations, including transvaginal ultrasonography and histological examination, confirmed adenocarcinoma. Imaging studies (magnetic resonance imaging [MRI] and computed tomography [CT]) revealed a thickened endometrium (11 mm) with no myometrial invasion, enlarged pelvic lymph nodes, or distant metastasis. Tumor markers were within normal ranges. She underwent robot-assisted laparoscopic total hysterectomy, bilateral adnexectomy, and pelvic lymph node biopsy using the da Vinci Xi system (Intuitive Surgical, Sunnyvale, CA). Histopathological examination revealed CHEC, with characteristic epithelioid and spindled cells arranged in cords within a hyalinized stroma. Immunohistochemical staining showed focal positivity for cytokeratin AE1/AE3, weak estrogen receptor positivity, and nuclear ß-catenin expression, distinguishing it from carcinosarcoma. The diagnosis was confirmed as CHEC, FIGO 2008 stage IA (pT1aN0M0). The patient remained disease-free 18 months post-surgery. CHEC is a rare variant of endometrioid carcinoma with unique histological features. It typically presents in younger patients at an early stage and has a favorable prognosis. Accurate diagnosis is crucial to differentiate it from more aggressive tumors like carcinosarcoma, preventing overtreatment. The immunohistochemical profile, particularly nuclear ß-catenin accumulation, is useful in distinguishing CHEC from carcinosarcoma. This is the first documented case of CHEC successfully treated with robot-assisted surgery. Increased awareness among pathologists and clinicians is essential for accurate diagnosis and optimal management of this rare tumor variant.

Predicting recurrence in intermediate­ and high­risk stage IB­IIB cervical cancer treated with adjuvant cisplatin and paclitaxel chemotherapy post­radical hysterectomy: The role of TBX2 expression.

Cervical cancer remains a significant global health concern despite advances in prevention and treatment. Current management for intermediate- to high-risk stage IB-IIB cervical cancer post-radical hysterectomy involves irradiation or concurrent chemoradiation, although patients can exhibit several adverse events. Adjuvant chemotherapy has emerged as a promising alternative; however, its efficacy remains unclear. T-box (TBX)2 is a transcription factor that is involved in the regulation of cell cycle progression during cancer and embryonic development. Additionally, elevated expression of TBX2 is associated with resistance to DNA-damaging chemotherapeutic agents, such as cisplatin, carboplatin and doxorubicin. The aim of the present study was to investigate the relationship between TBX2 expression and recurrence in patients receiving adjuvant cisplatin and paclitaxel (TP) chemotherapy post-radical hysterectomy. Additionally, the impact of TBX2 knockdown on cisplatin sensitivity was assessed in vitro. A retrospective analysis was performed on 100 patients. Patients were categorized into two groups based on recurrence within 2 years of treatment initiation: The non-recurrent group (n=85) and the recurrent group (n=15). TBX2 expression was assessed immunohistochemically, and multiple logistic regression analysis was performed to identify predictors of recurrence. Additionally, the impact of small interfering RNA-mediated TBX2 knockdown on cervical cancer cell sensitivity to cisplatin was evaluated. TBX2 expression was significantly higher in the recurrent group compared with that in the non-recurrent group (P<0.01). Patients were stratified into low TBX2 expression (weighted score ≤8; n=80) and high TBX2 expression (weighted score ≥9; n=20) groups. The high TBX2 expression group exhibited a higher recurrence rate compared with the low expression group (P<0.01). Multivariate analysis identified TBX2 expression as an independent predictor of recurrence (P<0.01). Moreover, TBX2 knockdown significantly enhanced cervical cancer cell sensitivity to cisplatin in vitro (P<0.05). These findings highlight TBX2 expression as a potential predictive biomarker for recurrence amongst patients with intermediate- to high-risk stage IB-IIB cervical cancer receiving adjuvant TP chemotherapy post-radical hysterectomy.

Role of Fyn expression in predicting the sensitivity to platinum­based chemotherapy in patients with ovarian serous carcinoma.

Ovarian serous carcinoma is a gynecological malignancy associated with a high mortality rate, which is commonly diagnosed in the first instance at a late stage and has a propensity to develop resistance to platinum-based chemotherapy. Identifying reliable biomarkers for platinum sensitivity is critical for improving patient outcomes. The present retrospective study included 64 patients with high-grade serous ovarian carcinoma (Federation of Gynecology and Obstetrics stages III or IV). Patients were classified as platinum-sensitive (no relapse within 6 months of the last platinum administration) or platinum-resistant (relapse within 6 months). Immunohistochemical analysis was performed to evaluate Fyn expression in tumor tissues, and Fyn knockdown experiments were performed using the OVSAHO ovarian cancer cell line to assess carboplatin sensitivity. Fyn expression was significantly higher in platinum-resistant patients compared with in platinum-sensitive patients (P<0.01). A weighted Fyn expression score was developed and a cutoff score of 6 was determined to predict platinum sensitivity with a specificity of 65.5% and a sensitivity of 62.9%. Patients with low Fyn expression (score ≤6) exhibited higher platinum sensitivity and longer overall survival (P<0.05). Multivariate analysis identified Fyn expression and postoperative residual tumor size as independent predictors of platinum sensitivity (P=0.033 and P=0.023, respectively). In vitro, Fyn knockdown significantly increased carboplatin sensitivity in ovarian cancer cells (P<0.05). Fyn, a member of the Src family of kinases, serves a crucial role in various cellular functions and has been implicated in chemotherapy resistance. The results demonstrated a notable association between Fyn expression and platinum sensitivity in ovarian serous carcinoma. The findings suggested that Fyn may serve as a predictive biomarker for response to platinum-based chemotherapy, offering the potential for more personalized treatment strategies. To the best of our knowledge, the present study is the first to establish an association between Fyn expression and platinum sensitivity in advanced ovarian serous carcinoma. Prospective studies with larger, multi-center cohorts and comprehensive biomarker analyses are recommended to validate and extend these results, ultimately improving therapeutic strategies and patient prognosis.

CLPTM1L expression predicts recurrence of patients with intermediate­ and high­risk stage IB­IIB cervical cancer undergoing radical hysterectomy followed by TP as adjuvant chemotherapy.

According to the National Comprehensive Cancer Network clinical practice guidelines of cervical cancer, concurrent chemoradiotherapy or radiotherapy is suggested for patients who receive radical hysterectomy and have intermediate- and high-risk cervical cancer. However, adjuvant chemotherapy has been increasingly chosen given the adverse events associated with chemoradiotherapy or radiotherapy and the increase in evidence regarding the efficacy of adjuvant chemotherapy. Given that adjuvant chemotherapy is not a standard treatment at present, if recurrence after adjuvant chemotherapy could be predicted, it would assist the decision of gynecological oncologists selecting which adjuvant therapy (chemotherapy or radiation therapy) to use. Cleft lip and palate transmembrane protein 1-like protein (CLPTM1L; also known as cisplatin resistance-related protein 9) is associated with apoptotic mechanisms and is related to the proliferation of the tumor cells and resistance against chemotherapy. In the present study, the association between CLPTM1L expression and recurrence of intermediate- and high-risk stage IB-IIB cervical cancer in patients undergoing radical hysterectomy followed by treatment with cisplatin and paclitaxel (TP) as adjuvant chemotherapy was determined. Patients were divided into two groups: Recurrence group and no-recurrence group. CLPTM1L expression was examined using immunohistochemistry in paraffin-embedded sections using weighted scores. Regarding the characteristics of the patients, a histology of non-squamous cell carcinoma, lymph node metastasis and parametrium invasion were more common in the recurrence group compared with the non-recurrence group. In the recurrence group, CLPTM1L expression was significantly higher than that in the no-recurrence group. Next, patients were divided into low and high-expression groups based on the weighted score with a cut-off value of 6. In the high expression group, patients exhibited a higher rate of recurrence (37.5 vs. 5.1%) and had worse overall survival. Multivariate analysis revealed that high CLPTM1L expression was independently related to recurrence. In in vitro analysis, small interfering RNA-mediated knockdown of CLPTM1L enhanced the sensitivity of cervical cancer cells to cisplatin. In conclusion, the present study revealed that CLPTM1L expression may be a predictive biomarker of recurrence of intermediate- and high-risk stage IB-IIB cervical cancer in patients undergoing radical hysterectomy followed by TP as adjuvant chemotherapy.

Intestinal­type mucinous carcinoma of the endometrium showing a polypoidal exophytic form: A case report.

Although endometrial cancer is a common malignancy in women, rare histological subtypes can pose diagnostic challenges. Primary endometrial intestinal-type mucinous carcinoma is a newly recognized subtype of endometrial cancer that differs from Müllerian-type endometrial mucinous carcinoma. The present case report documents a rare case of intestinal-type mucinous carcinoma of the endometrium showing a polypoidal exophytic form. The patient, an 80-year-old female, was incidentally diagnosed with a uterine tumor during a follow-up for vulvar Paget's disease. Clinical and imaging examinations revealed a localized mass within the uterine cavity. Hysteroscopy and subsequent histological examination confirmed the presence of intestinal-type mucinous carcinoma of the endometrium. Microscopically, the tumor displayed adenocarcinoma containing an intestinal-type glandular epithelium with mild nuclear atypia. It stained positive for the gastrointestinal markers mucin 2 and caudal type homeobox 2, and stained negatively for estrogen receptor α. The patient underwent surgery and adjuvant chemotherapy, with no evidence of recurrence at the latest follow-up 6 months after surgery. Endometrial intestinal-type mucinous carcinoma is a rare histological subtype of endometrial cancer. Differential diagnoses include Müllerian-type endometrial mucinous carcinoma, endocervical adenocarcinoma, metastasis from gastrointestinal tract adenocarcinoma and non-neoplastic gastric/intestinal metaplasia. However, the prognosis of endometrial intestinal-type mucinous carcinoma remains unclear due to limited reported cases. Existing evidence suggests a poorer prognosis compared with classical mucinous carcinomas of the endometrium. The present case, which is characterized by a polypoidal exophytic tumor without myometrial invasion, showed a favorable outcome. Further documentation and characterization of the aforementioned rare malignancy are necessary to enhance the understanding of its clinical physiology and outcomes. The present case report highlights the diagnostic challenges associated with intestinal-type mucinous endometrial carcinoma. The inclusion of this type of malignancy in the latest World Health Organization classification emphasizes the need for further comprehensive studies and case reports to expand the current knowledge on this rare histological subtype.

Carcinomatous meningitis from ovarian serous carcinoma: A case report.

Multifocal dissemination of cancer cells from the primary tumor sites to the subarachnoid, pia mater and cerebrospinal fluid (CSF) of the brain and spinal cord causes carcinomatous meningitis (CM). CM is rarely observed in patients with gynecological cancer. The present study described a 59-year-old woman who was diagnosed with CM as a recurrence of stage IIIC ovarian cancer, after presenting with headache and decreased level of consciousness. During adjuvant therapy following surgical debulking, she developed nausea and vomiting. The post-contrast fluid-attenuated inversion-recovery magnetic resonance imaging showed leptomeningeal enhancement on all sulci, particularly around the falx cerebri and cerebellar hemisphere. CM was suspected and CSF cytology revealed adenocarcinoma cells, thus confirming the diagnosis. Overall, although CM is rare, clinicians should be aware of this complication when patients with malignancies experience neurological symptoms, including headache, nausea and vomiting. Knowledge of this clinical entity should assist clinicians in ascertaining accurate diagnoses.

Real-world Efficacy and Safety of Bevacizumab for Advanced or Recurrent Müllerian Cancer: A Single-institutional Experience.

BACKGROUND/AIM: The efficacy and safety of bevacizumab for ovarian cancer have been reported in randomized phase III clinical trials. It is important to gather experience and data in a real-world setting. The objective of the present study was to evaluate the efficacy and safety of bevacizumab for patients with ovarian cancer in a real-world setting. PATIENTS AND METHODS: For front-line settings, patients with FIGO stage III-IV ovarian cancer treated using bevacizumab and chemotherapy after debulking surgery (Chemo + Bev group, n=79), in addition to those treated with only chemotherapy after debulking surgery (Chemo group; n=66), at our institute were reviewed retrospectively. For recurrent settings, patients with recurrent ovarian cancers treated with bevacizumab and any chemotherapy were reviewed retrospectively (n=65). RESULTS: In the front-line setting, the disease-free survival was significantly longer in the Chemo + Bev group compared with that in the Chemo group (p=0.021). Hypertension and proteinuria were found to be statistically more frequent in the Chemo + Bev group compared with that in the Chemo group (p=0.002 and p=0.004). In the recurrent setting, in platinum-sensitive patients, the response rate (RR) and the disease control ratio (DCR) were 78.4 and 94.1%, respectively. In platinum-resistant patients, the RR and the DCR were 28.6 and 57.1% respectively. The median progression-free survival was 18.3 and 7.1 months for platinum-sensitive recurrence and platinum-resistant recurrence, respectively. The major ≥ grade 3 adverse event was neutropenia. CONCLUSION: The present study provided encouraging real-world evidence of the efficacy and safety of bevacizumab for ovarian cancer in real-world.

A difficult to diagnose case of low-grade endometrial stromal sarcoma with smooth muscle differentiation treated with laparoscopic surgery: A case report.

Low-grade endometrial stromal sarcoma (LGESS) is a rare uterine tumor, accounting for <1% of all uterine cancer cases. LGESS has several variations and the frequency of tumors exhibiting smooth muscle differentiation is 10-30% of LGESS cases, making such cases even rarer. The present report described the case of a patient with LGESS with smooth muscle differentiation, who was diagnosed as having uterine leiomyoma by preoperative needle biopsy and then underwent laparoscopic surgery. The patient was a 41-year-old woman. MRI findings revealed a diffusely hyperintense uterine tumor on T2-weighted images, thus needle biopsy was performed. This tumor was initially diagnosed as leiomyoma, due to the pathological findings of the biopsied specimen, which possessed tumor cells with spindle-shaped nuclei arranged in a cord and positive immunostaining for smooth muscle actin. The patient was subsequently followed up, and MRI findings after 29 months showed tumor growth. Needle biopsy was performed again and the findings were the same as those of the first biopsy; therefore, this tumor was diagnosed as a leiomyoma and laparoscopic hysterectomy was performed. However, the pathological findings of the excised uterus showed small round tumor cells and CD10 immunostaining positivity, thus the tumor was finally diagnosed as LGESS. The patient requested to be followed up and has shown no signs of recurrence 20 months after surgery. The results of retrospective examination in this case suggested that the presence of regions where only CD10 was positive in immunostaining analysis for SMA and CD10 was useful for needle biopsy diagnosis of LGESS with smooth muscle differentiation.

Surface modification of the cubic micro-cartilage by collagenase treatment and its efficacy in cartilage regeneration for ear tissue engineering.

BACKGROUND: In order to enhance cartilage regeneration, surface modification of the cubic micro-cartilage with the collagenase treatment was tested and its efficacy to tissue engineer ear cartilage was investigated. MATERIALS AND METHODS: Harvested cubic micro-cartilages were treated with collagenase with different digestion time (0, 15, 60, and 120 min). Histological, ultrastructural (SEM and TEM), and Western blot analyses were carried out. Subsequently, A total of 45 dogs were used to tissue engineer ear cartilage. Using collagenase-treated micro-cartilage, the ear cartilage regeneration with the prepared dilution (8, 12.5, 25, 50, 100%) of micro-cartilage block seeding was performed to determine the minimum amount of cartilage tissue required for ear tissue-engineering (n = 6 at each point in each group). At 10 weeks after surgery, samples were resected and subjected to histochemical and immune-histological evaluation for cartilage regeneration. RESULTS: In vitro study on micro-cartilage morphology and western blot analysis showed that collagenase digestion was optimal at 60 min for cartilage regeneration. In vivo evaluation on the reduced proportions of micro-cartilage block seeding onto implant scaffolds under 60-min collagenase digestion determined the minimum amount of cartilage tissue necessary to initiate a one-step ear cartilage regeneration in a canine autologous model, which was 12.5-25% of the original ear size. CONCLUSION: Tissue-engineering ear cartilage from limited volume of donor cartilage can possibly be achieved by the collagenase treatment on micro-cartilage to expand cartilage regeneration capacity, application of cytokine sustained-release system, and seeding on a suitable ear scaffold material.

Fyn expression is associated with the response of patients with locally advanced uterine cervical squamous cell carcinoma to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) followed by surgery is the current standard of treatment for locally advanced uterine cervical cancer; however, its value and outcomes remain contested. Identifying biomarkers that allow for the prediction of the effect of NAC efficacy before initiation of treatment is essential, in order to assist in choosing the optimum therapeutic regimen to maximize the beneficial outcomes of treatment. In the present retrospective study, 44 patients with locally advanced uterine cervical squamous cell carcinoma who underwent NAC were divided into two groups: A NAC successful group and a NAC failure group, depending on the efficacy of NAC. Subsequently, the association between Fyn expression, a non-receptor tyrosine kinase that is a member of the Src family kinases, and NAC efficacy was determined; Fyn expression was detected by immunohistochemistry and assessed using a weighted scoring method. Additionally, the effect of Fyn knockdown on the sensitivity of a uterine cervical cancer cell line to cisplatin was determined. Notably, there were no significant differences between the two groups of patients regarding their characteristics. Regarding overall survival, the NAC successful group had a significantly longer survival time than the NAC failure group (P=0.01). Furthermore, the expression levels of Fyn in tumor tissues were significantly lower in the NAC successful group compared with those in the NAC failure group (P=0.003). The patients were subsequently divided into two groups (high expression group and low expression group) according to a cutoff value of 3, which was determined by producing a receiver operating characteristic curve from the weighted scores. The low expression group was significantly more sensitive to NAC than the high expression group (P<0.001). In vitro experiments revealed that Fyn knockdown significantly enhanced the sensitivity of uterine cancer cells to cisplatin (P<0.05). In conclusion, Fyn expression may be a potentially useful biomarker for predicting the response to NAC in patients with locally advanced uterine cervical squamous cell carcinoma, and may also be a promising molecular target for the management of uterine cancer.

Massive ovarian edema with paraovarian cyst torsion treated with laparoscopic surgery: A case report.

Massive ovarian edema is a rare gynecological entity resembling a solid ovarian tumor due to the accumulation of edematous fluid within the ovarian stroma. This condition can be easily mistaken for a neoplasm, resulting in overtreatment by removal of the whole affected ovary. The present study describes the case of a 28-year-old woman who experienced massive ovarian edema with paraovarian cyst torsion treated with laparoscopic surgery. The patient experienced lower abdominal pain lasting for 1 week and visited a local clinic. The ultrasonographic examination revealed two loculated ovarian masses and the patient was then referred to the hospital. Transvaginal ultrasonographic examination revealed a 77.9-mm cystic lesion and a 57.7-mm solid lesion in the left adnexa. A magnetic resonance imaging examination revealed a 55-mm lesion with multiple peripheral ovarian follicles, which was isointense on T1-weighted images and hyperintense on T2-weighted images, and a 75-mm cystic lesion, without a solid component, which was hypointense on T1-weighted images and hyperintense on T2-weighted images in the left adnexa. There were no observed abnormalities of the right adnexa or uterus. Laparoscopic surgery was performed, based on a clinical suspicion of massive ovarian edema with paraovarian cyst torsion. Intraoperatively, a paraovarian cyst was identified in the left adnexa that was twisted 360˚. The size of the enlarged left ovary was reduced to almost normal following the detorsion of the left adnexa. The final diagnosis was that of a massive ovarian edema, which was treated by resecting the paraovarian cyst, while preserving the whole left ovary. The pathological examination of the resected paraovarian cyst revealed a serous cystadenoma. Therefore, the present study suggests that the presence of massive ovarian edema should be taken into consideration when encountering a complex solid ovarian mass with multiple peripheral ovarian follicles, particularly in cases with a history of recurrent abdominal pain.

PRMT1 expression predicts response to neoadjuvant chemotherapy for locally advanced uterine cervical cancer.

The standard care for patients with locally advanced cervical cancer is concurrent chemoradiotherapy. Successful neoadjuvant chemotherapy (NAC) can reduce tumor size and enable patients to be eligible for a hysterectomy, which can improve their prognosis. Selecting the right candidate for NAC is important since NAC failure results in switching to radiation therapy and can lead to a worse prognosis due to a delay in the initiation of the core therapy. Therefore, the identification of biomarkers that can predict the effect of NAC is essential. Previous reports have suggested a relationship between protein arginine methyltransferase (PRMT1) and chemoresistance in several types of cancer. PRMT1 has been demonstrated to methylate apoptosis signal-regulated kinase 1 and to inhibit its activity, thereby contributing to chemoresistance. The present study investigated the association between PRMT1 expression and the efficacy of NAC in locally advanced cervical cancer. Data from 53 patients with locally advanced uterine cervical cancer who were classified into two groups based on effective (n=28) and ineffective (n=25) responses to NAC treatment were evaluated. PRMT1 expression was investigated by immunohistochemistry and scored using a weighted scoring system. Additionally, the present study investigated the effect of RNA interference-mediated downregulation of PRMT1 on the sensitivity of cervical cancer cells to cisplatin in vitro. The results demonstrated that the NAC effective group had significantly lower weighted PRMT1 scores than the NAC ineffective group (P=0.030). In addition, lower tumor expression levels of PRMT1 were significantly associated with increased sensitivity to NAC (P=0.033). Furthermore, downregulation of PRMT1 expression in cervical cancer cells markedly improved their sensitivity to cisplatin in vitro. The present study suggested that PRMT1 expression has potential as a predictive marker of the efficacy of NAC in patients with locally advanced cervical cancer. This finding can contribute to improvements in the prognosis of these patients.

PRMT1 expression predicts sensitivity to platinum-based chemotherapy in patients with ovarian serous carcinoma.

Patients with ovarian serous carcinoma are generally diagnosed at an advanced disease stage. The standard treatment for these patients is maximal debulking surgery followed by platinum-taxane combination chemotherapy. Despite initially responding well, more than half of patients become refractory to first-line chemotherapy. Upregulation of protein arginine methyltransferase 1 (PRMT1) expression has been demonstrated to methylate apoptosis signal-regulated kinase 1 and inhibit its activity, thereby contributing to chemoresistance. The present study investigated the association between PRMT1 expression and sensitivity to platinum-based chemotherapy in 51 patients with ovarian serous carcinoma (International Federation of Gynecology and Obstetrics stages III and IV), and the effect of RNA interference-mediated downregulation of PRMT1 on the sensitivity of ovarian cancer cells to cisplatin and carboplatin in vitro. Immunohistochemistry of tumor specimens was used to compare the expression levels of PRMT1, a Cell Counting Kit-8 assay and small interfering RNA transfection were performed for chemosensitivity assays, and reverse transcription-quantitative PCR was used to examine PRMT1 mRNA expression. Patients were divided into platinum-sensitive (n=26) and platinum-resistant (n=25) groups. PRMT1 expression was significantly lower in the platinum-sensitive group than in the platinum-resistant group (P=0.019). When patients were categorized according to PRMT1 expression, those in the low PRMT1 expression group were more sensitive to platinum-based chemotherapy than those in the high PRMT1 expression group (P=0.01). Additionally, in vitro experiments revealed that suppression of PRMT1 expression by siRNA significantly increased the sensitivity of human ovarian serous carcinoma cells to cisplatin and carboplatin (P<0.05). In conclusion, PRMT1 expression could predict sensitivity to platinum-based chemotherapy in patients with ovarian serous carcinoma.

T-box 2 expression is a useful indicator of the response to neoadjuvant chemotherapy for patients with locally advanced uterine cervical squamous cell carcinoma.

Platinum-based concurrent chemoradiotherapy is the standard treatment for patients with locally advanced uterine cervical squamous cell carcinoma. Reducing the tumor size by administering neoadjuvant chemotherapy (NAC) is beneficial for successful hysterectomy, resulting in a more favorable prognosis. Therefore, identifying biomarkers that predict the effectiveness of NAC in patients with cervical squamous cell carcinoma remains a priority. Cancer cells widely express T-box 2 (TBX2), which contributes to the resistance to DNA-damaging chemotherapeutic agents. The present study aimed to determine the association between TBX2 protein expression in tumor tissues and the efficacy of NAC in locally advanced uterine cervical squamous cell carcinoma using immunohistochemistry. Data from 46 patients with locally advanced uterine cervical squamous cell carcinoma were classified into two groups based on their effective or ineffective response to NAC treatment. In addition, the effect of small interfering RNA-mediated knockdown of TBX2 on the sensitivity of cervical cancer cells to cisplatin was investigated in vitro. The results revealed that there were no significant differences in patient clinicopathological features between the NAC effective and NAC ineffective groups. The overall survival of the NAC effective group was significantly improved compared with the NAC ineffective group (P=0.007). Tumors from the NAC effective group also had significantly downregulated TBX2 expression levels compared with those from the NAC ineffective group (P=0.0138). Of note, decreased TBX2 expression was indicated to be significantly associated with higher sensitivity to NAC (P=0.009). The low TBX2 expression group had a more favorable overall survival compared with the high TBX2 expression group (P=0.049). Furthermore, knockdown of TBX2 expression significantly increased cancer cell sensitivity to cisplatin in vitro. In conclusion, the results of the present study suggested that TBX2 expression may be a useful predictor of the response to NAC in patients with locally advanced uterine cervical squamous cell carcinoma.

Uterine metastasis of lobular breast carcinoma under tamoxifen therapy: A case report.

Uterine metastases from breast cancer are uncommon and have rarely been reported in the previous literature. The present report describes the case of a 66-year-old female who developed uterine metastasis 23 years following the primary treatment of invasive breast cancer. Specifically, the patient experienced multiple bone metastases 14 years following primary treatment and had previously been treated with aromatase inhibitors followed by tamoxifen citrate. The patient presented with abnormal genital bleeding and was referred to the Gynecology Department of the Osaka City University Hospital (Osaka, Japan) 23 years following the primary treatment. The results of an endometrial biopsy revealed adenocarcinoma. Initially, it was difficult to differentiate between primary endometrial adenocarcinoma and metastatic adenocarcinoma from breast cancer. The results of pelvic magnetic resonance imaging demonstrated uterine myometrium enlargement and no endometrial thickness. Furthermore, an abdominal total hysterectomy, bilateral salpingo-oophorectomy and a biopsy of the peritoneum were performed. The pathological examination of the resected uterus revealed adenocarcinoma, which proliferated diffusively in the cervical stroma, myometrium, cardinal ligament, bilateral adnexa, omentum and peritoneum. Immunohistochemical results revealed the positive staining of gross cystic disease fluid protein-15, as well as negative staining for CD10 and E-cadherin. Thus, the tumor was diagnosed as metastatic adenocarcinoma from the breast lobular carcinoma. The patient has since been treated with fulvestrant, toremifene citrate and tegafur, and the current patient survival duration is 2 years and 8 months. In conclusion, when patients with breast cancer undergoing hormonal therapy, such as tamoxifen, present with abnormal genital bleeding, future diagnoses should consider both endometrial cancer and uterine metastasis from breast cancer.

Neutrophil-to-lymphocyte ratio is associated with sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

The role of the neutrophil-to-lymphocyte ratio (NLR) in predicting sensitivity to chemotherapy and prognosis has attracted great interest in several types of cancer. In the present study, the correlation between pre-chemotherapy NLR and sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma was examined by retrospectively reviewing the medical records of 50 patients with stage III-IV serous ovarian carcinoma from 2005 to 2012. Patients were divided into high-NLR (32 patients) and low-NLR (18 patients) groups according to a cutoff value of 2.47. This cutoff was calculated using a receiver operating characteristic (ROC) curve that demonstrated 84% specificity and 60% sensitivity. Patient characteristics, sensitivity to platinum-based chemotherapy and prognosis were subsequently compared. The results revealed no significant difference in patient characteristics between the two groups. In the low-NLR group, 14 of 18 patients (77.8%) were sensitive to platinum-based chemotherapy, whereas 11 of 32 were sensitive in the high-NLR group (34.4%) (P=0.007). Overall and disease-free survival (DFS) were significantly longer in the low-NLR than in the high-NLR group (P=0.013 and P=0.043, respectively). The current results suggested that pre-chemotherapeutical NLR may serve as a biomarker of sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

Clinical benefit for clinical sequencing using cancer panel testing.

BACKGROUND: Clinical sequencing using a panel of genes has recently been applied worldwide for patients with refractory solid tumors, but the significance of clinical sequencing using gene panel testing remains uncertain. Here we sought to clarify the feasibility and utility of clinical sequencing in the treatment of refractory tumors at our hospital. METHODS: A total of 39 patients with advanced solid tumors treated at our hospital between 2018 and 2020 were enrolled in the clinical sequencing. Among them, we identified 36 patients whose tissue samples were of suitable quality for clinical sequencing, and we analyzed the genomic profiles of these tumors. RESULTS: Pathogenic alterations were detected in 28 (78%) of the 36 patients. The most common mutation was TP53 (55%), followed by KRAS (22%), and the highest frequency of gene amplification was ERBB2 (17%). Nine of the 36 patients were identified as candidates for novel molecular-targeted therapy based on their actionable gene alterations, but only one case ended up receiving novel targeted therapy following the genetic tests. CONCLUSIONS: Our current results suggested that clinical sequencing might be useful for the detection of pathogenic alterations and the management of additional cancer treatment. However, molecular target based on actionable genomic alteration does not always bridge to subsequent therapy due to clinical deterioration, refusal for unapproved drug, and complexity of clinical trial access. Both improved optimal timing of clinical sequencing and a consensus about its off-label use might help patients receive greater benefit from clinical sequencing.